15-hydroxy-11-alpha-9-alpha-(epoxymethano)prosta-5-13-dienoic-acid and Hyperlipidemias

We characterized the acute effects of oxidized low-density lipoproteins (oxidized-LDL) on vascular reactivity in isolated aorta from wild-type C57BL/6J mice, and compared these with the chronic alterations in vascular function observed in apolipoprotein-E gene knockout [ApoE(-/-)] mice fed a high-fat diet, which results in hyperlipidemia and atherosclerosis. In the abdominal (but not thoracic) aorta, oxidized-LDL (100 microg/ml) reduced relaxations induced by acetylcholine (10(-9) M-10(-5) M), which are mediated entirely by nitric oxide (NO). The relaxations induced by the NO donor S-nitroso-N-acetylpenicillamine (SNAP, 10(-8) M-10(-4) M), the cyclic GMP analogue 8-bromo cyclic GMP (100 microM) and the nonspecific vasodilator papaverine (100 microM) were not changed by oxidized-LDL. Native LDL had no effect on vasorelaxations. The attenuation of endothelium-dependent relaxations caused by oxidized-LDL mimicked the endothelial dysfunction found in ApoE(-/-) mice. These results are consistent with the suggestion that oxidized-LDL has an important role in the pathogenesis of endothelial NO dysfunction associated with hyperlipidemia and atherosclerosis in these mice.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Animals; Aorta, Abdominal; Aorta, Thoracic; Apolipoproteins E; Arteriosclerosis; Cholesterol, Dietary; Dose-Response Relationship, Drug; Endothelium, Vascular; Genotype; Hyperlipidemias; In Vitro Techniques; Lipoproteins, LDL; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide Donors; Penicillamine; Potassium; Serotonin; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents